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The UK Biobank has made general practitioner (GP) data (censoring date 2016–2017) available for approximately 45% of the cohort, whilst hospital inpatient and death registry (referred to as "HES/Death") data are available cohort-wide through 2018–2022 depending on whether the data comes from England, Wales or Scotland. We assessed the importance of case ascertainment via different data sources in UKB for three diseases that are usually first diagnosed in primary care: Parkinson's disease (PD), type 2 diabetes (T2D), and all-cause dementia. Including GP data at least doubled the number of incident cases in the subset of the cohort with primary care data (e.g. from 619 to 1390 for dementia). Among the 786 dementia cases that were only captured in the GP data before the GP censoring date, only 421 (54%) were subsequently recorded in HES. Therefore, estimates of the absolute incidence or risk-stratified incidence are misleadingly low when based only on the HES/Death data. For incident cases present in both HES/Death and GP data during the full follow-up period (i.e. until the HES censoring date), the median time difference between an incident diagnosis of dementia being recorded in GP and HES/Death was 2.25 years (i.e. recorded 2.25 years earlier in the GP records). Similar lag periods were also observed for PD (median 2.31 years earlier) and T2D (median 2.82 years earlier). For participants with an incident GP diagnosis, only 65.6% of dementia cases, 69.0% of PD cases, and 58.5% of T2D cases had their diagnosis recorded in HES/Death within 7 years since GP diagnosis. The effect estimates (hazard ratios, HR) of established risk factors for the three health outcomes mostly remain in the same direction and with a similar strength of association when cases are ascertained either using HES only or further adding GP data. The confidence intervals of the HR became narrower when adding GP data, due to the increased statistical power from the additional cases. In conclusion, it is desirable to extend both the coverage and follow-up period of GP data to allow researchers to maximise case ascertainment of chronic health conditions in the UK. [ABSTRACT FROM AUTHOR]

Currently, no disease-modifying therapies are approved for osteoarthritis (OA) use. One obstacle to trial success in this field has been our existing endpoints' limited validity and responsiveness. To overcome this impasse, the Foundation for the NIH OA Biomarkers Consortium is focused on investigating biomarkers for a prognostic context of use for subsequent qualification through regulatory agencies. This narrative review describes this activity and the work underway, focusing on the PROGRESS OA study. [ABSTRACT FROM AUTHOR]

A joint contains many different tissues that can exhibit pathological changes, providing many potential targets for treatment. Researchers are increasingly suggesting that osteoarthritis (OA) comprises several phenotypes or subpopulations. Consequently, a treatment for OA that targets only one pathophysiologic abnormality is unlikely to be similarly efficacious in preventing or delaying the progression of all the different phenotypes of structural OA. Five structural phenotypes have been proposed, namely the inflammatory, meniscus-cartilage, subchondral bone, and atrophic and hypertrophic phenotypes. The inflammatory phenotype is characterized by marked synovitis and/or joint effusion, while the meniscus-cartilage phenotype exhibits severe meniscal and cartilage damage. Large bone marrow lesions characterize the subchondral bone phenotype. The hypertrophic and atrophic OA phenotype are defined based on the presence large osteophytes or absence of any osteophytes, respectively, in the presence of concomitant cartilage damage. Limitations of the concept of structural phenotyping are that they are not mutually exclusive and that more than one phenotype may be present. It must be acknowledged that a wide range of views exist on how best to operationalize the concept of structural OA phenotypes and that the concept of structural phenotypic characterization is still in its infancy. Structural phenotypic stratification, however, may result in more targeted trial populations with successful outcomes and practitioners need to be aware of the heterogeneity of the disease to personalize their treatment recommendations for an individual patient. Radiologists should be able to define a joint at risk for progression based on the predominant phenotype present at different disease stages. [ABSTRACT FROM AUTHOR]

Introduction: Globally, the rate of opioid prescription is high for chronic musculoskeletal conditions despite guidelines recommending against their use as their adverse effects outweigh their modest benefit. Deprescribing opioids is a complex process that can be hindered by multiple prescriber- and patient-related barriers. These include fear of the process of, or outcomes from, weaning medications, or a lack of ongoing support. Thus, involving patients, their carers, and healthcare professionals (HCPs) in the development of consumer materials that can educate and provide support for patients and HCPs over the deprescribing process is critical to ensure that the resources have high readability, usability, and acceptability to the population of interest. Objective: This study aimed to (1) develop two educational consumer leaflets to support opioid tapering in older people with low back pain (LBP) and hip or knee osteoarthritis (HoKOA), and (2) evaluate the perceived usability, acceptability, and credibility of the consumer leaflets from the perspective of consumers and HCPs. Design: This was an observational survey involving a consumer review panel and an HCP review panel. Participants: 30 consumers (and/or their carers) and 20 HCPs were included in the study. Consumers were people older than 65 years of age who were currently experiencing LBP or HoKOA, and with no HCP background. Carers were people who provided unpaid care, support, or assistance to an individual meeting the inclusion criteria for consumers. HCPs included physiotherapists (n = 9), pharmacists (n = 7), an orthopaedic surgeon (n = 1), a rheumatologist (n = 1), nurse practitioner (n = 1) and a general practitioner (n = 1), all with at least three years of clinical experience and who reported working closely with this target patient population within the last 12 months. Methods: Prototypes of two educational consumer leaflets (a brochure and a personal plan) were developed by a team of LBP, OA, and geriatric pharmacotherapy researchers and clinicians. The leaflet prototypes were evaluated by two separate chronological review panels involving (1) consumers and/or their carers, and (2) HCPs. Data collection for both panels occurred via an online survey. Outcomes were the perceived usability, acceptability, and credibility of the consumer leaflets. Feedback received from the consumer panel was used to refine the leaflets, before circulating the leaflets for further review by the HCP panel. Additional feedback from the HCP review panel was then used to refine the final versions of the consumer leaflets. Results: Both consumers and HCPs perceived the leaflets and personal plan to be usable, acceptable, and credible. Consumers rated the brochure against several categories, which scored between 53 and 97% positive responses. Similarly, the overall feedback provided by HCPs was 85–100% positive. The modified System Usability Scale scores obtained from HCPs was 55–95% positive, indicating excellent usability. Feedback for the personal plan from both HCPs and consumers was largely positive, with consumers providing the highest positive ratings (80–93%). While feedback for HCPs was also high, we did identify that prescribers were hesitant to provide the plan to patients frequently (no positive responses). Conclusions: This study led to the development of a leaflet and personal plan to support the reduction of opioid use in older people with LBP or HoKOA. The development of the consumer leaflets incorporated feedback provided by HCPs and consumers to maximise clinical effectiveness and future intervention implementation. Plain Language Summary: Opioids are medications that are often used to treat severe or chronic pain. However, they can have serious adverse effects and are not usually recommended for long-term use. This study aimed to create educational materials for patients with chronic low back pain or hip or knee osteoarthritis who are taking opioids and to evaluate the materials' perceived usability, acceptability, and credibility from the perspective of both healthcare professionals (HCPs) and patients. The materials included a brochure and a personal plan and were developed by a team of researchers and clinicians. Both materials were evaluated by HCPs and patients in separate review panels. The brochure and personal plan were found to be usable, acceptable, and credible by both groups. The materials were created to support patients in reducing their opioid use and were refined based on feedback from both HCPs and patients. The materials may be useful in supporting the complex process of tapering off opioids, which can be hindered by various barriers related to both patients and HCPs. [ABSTRACT FROM AUTHOR]

The lifetime risk of symptomatic hand osteoarthritis (OA) is 39.8%, with one in two women and one in four men developing the disease by age 85 years and no disease-modifying drug (DMOAD) available so far. Intra-articular (IA) therapy is one of the options commonly used for symptomatic alleviation of OA disease as it can circumvent systemic exposure and potential side effects of oral medications. The current narrative review focuses on the efficacy and safety profiles of the currently available IA agents in hand OA (thumb-base OA or interphalangeal OA) such as corticosteroids and hyaluronic acid (HA), as well as the efficacy and safety of IA investigational injectates in phase 2/3 clinical trials such as prolotherapy, platelet-rich plasma, stem cells, infliximab, interferon-? and botulinum toxin, based on the published randomized controlled trials on PubMed database. The limited published literature revealed the short-term symptomatic benefits of corticosteroids in interphalangeal OA while long-term data are lacking. Most of the short-term studies showed no significant difference between corticosteroids and hyaluronic acid in thumb-base OA, usually with a faster onset of pain relief in the corticosteroid group and a slower but greater (statistically insignificant) pain improvement in the HA group. The majority of studies in investigational agents were limited by small sample size, short-term follow-up, and presence of serious side effects. In addition, we reported higher accuracy rates of drug administrations under imaging guidance than landmark guidance (blind method), and then briefly describe challenges for the long-term efficacy and prospects of IA therapeutics. [ABSTRACT FROM AUTHOR]

Polygenic risk scores (PRS) are proposed for use in clinical and research settings for risk stratification. However, there are limited investigations on how different PRS diverge from each other in risk prediction of individuals. We compared two recently published PRS for each of three conditions, breast cancer, hypertension and dementia, to assess the stability of using these algorithms for risk prediction in a single large population. We used imputed genotyping data from the UK Biobank prospective cohort, limited to the White British subset. We found that: (1) 20% or more of SNPs in the first PRS were not represented in the more recent PRS for all three diseases, by the same SNP or a surrogate with R2 > 0.8 by linkage disequilibrium (LD). (2) Although the difference in the area under the receiver operating characteristic curve (AUC) obtained using the two PRS is hardly appreciable for all three diseases, there were large differences in individual risk prediction between the two PRS. For instance, for each disease, of those classified in the top 5% of risk by the first PRS, over 60% were not so classified by the second PRS. We found substantial discordance between different PRS for the same disease, indicating that individuals could receive different medical advice depending on which PRS is used to assess their genetic susceptibility. It is desirable to resolve this uncertainty before using PRS for risk stratification in clinical settings. [ABSTRACT FROM AUTHOR]

Metformin has been shown to modulate meta-inflammation, an important pathogenesis in knee osteoarthritis (OA). The study aimed to test the association between regular metformin use with total knee replacement (TKR) in patients with diabetes. This is a retrospective study with electronic records retrieved in Hong Kong public primary care. Patients with diabetes aged ≥ 45 who visited during 2007 to 2010, were followed up for a four-year period from 2011 to 2014 to determine the incidence of TKR. Propensity score matching based on age, sex, co-medications and chronic conditions was conducted to adjust for confounding. Cox regression was implemented to examine the association between metformin use and TKR. In total, 196,930 patients were eligible and 93,330 regular metformin users (defined as ≥ 4 prescriptions over the previous year) and non-users were matched. Among 46,665 regular users, 184 TKRs were conducted, 17.1% fewer than that among non-users. Cox regression showed that regular metformin users had a 19%-lower hazard of TKR [hazard ratio (HR) = 0.81, 95% confidence interval: 0.67 to 0.98, P = 0.033], with a dose–response relationship. Findings suggest a potential protective effect of metformin on knee OA progression and later TKR incidence among diabetic patients. [ABSTRACT FROM AUTHOR]

Objective: To explain the factors contributing to the gap in depression between employed arthritis patients with and without paid sick leave. Methods: Blinder-Oaxaca decomposition analysis was used to identify factors that explain the gap in the experience of depressive symptoms among arthritis patients with paid and unpaid sick leave. Data from the 2018 National Health Interview Survey, USA, was used. Results: A total of 7189 of the NHIS survey participants given the diagnosis of arthritis were identified, of which 39% were male and 61% were female, with mean age of 63.5 years. The decomposition findings suggest patients in the unpaid sick leave group were more likely to report depressive symptoms compared to patients with paid sick leave. The major contributors to the gap in the report of depressive symptoms are sex (female) and annual income (less than 35,000 USD). Conclusion: Findings suggest that the absence of paid sick leave is a key determinant for experiencing depressive symptoms among individuals with arthritis. The provision of paid sick leave may reduce report of depressive symptoms among employed arthritis patients in the USA. Key Points: • Individuals with arthritis are consistently at greater risk of depression and unemployment as compared to individuals without arthritis. • To date greater emphasis is put on determinants of unemployment, while there is no available data on benefits associated with being employed, such as sick leave, and how it affects mental health. • Patients with unpaid sick leave appear to experience more persistent depressive symptoms than patients with access to paid sick leave. • To tackle burden of depression among arthritis patients, provision of paid sick leave may be an effective intervention. [ABSTRACT FROM AUTHOR]

Objective: To determine whether pericruciate fat pad (PCFP) signal intensity alteration and maximal area are associated with incident radiographic osteoarthritis (ROA) over 4 years in the Osteoarthritis Initiative (OAI) study. Methods: Participants were from the Osteoarthritis Initiative (OAI) study. Case knees (n = 355) were defined by incident ROA between 12 and 48 months visits and were matched by sex, age, and radiographic status with control knees (n = 355). Magnetic resonance images (MRIs) were used to assess PCFP signal intensity alteration and PCFP maximal area at P0 (time of onset of ROA), P-1 (1 year prior to P0), and baseline. Conditional logistic regression analyses were applied to assess associations between PCFP measures and the risk of incident ROA. Results: The mean age of participants was 60.1 years and 66.9% were women. In multivariable analyses, PCFP signal intensity alteration measured at three time points (OR [95%CI]: 1.28 [1.10–1.50], 1.52 [1.30–1.78], 1.50 [1.27–1.76], respectively) and PCFP maximal area (OR [95%CI]: 1.21 [1.03–1.42], 1.27 [1.07–1.52], 1.37 [1.15–1.62], respectively) were significantly associated with incident ROA. Conclusions: PCFP signal intensity alteration and maximal area were associated with incident ROA over 4 years, implying that they may have roles to play in ROA. Key Points: • Pericruciate fat pad signal intensity alteration and maximal area were associated with incident ROA, implying that they may have roles to play in ROA. [ABSTRACT FROM AUTHOR]

Musculoskeletal pain such as osteoarthritis (OA) and low back pain (LBP) are very common and contribute to enormous burden and societal costs, despite dramatic therapeutic advances over recent decades. Novel approaches and targeted therapies are required to satisfy the urgent unmet medical need of musculoskeletal pain relief in both conditions. Nerve growth factor (NGF) inhibitors have utilized novel mechanisms different from conventional drugs, which have a variety of gastrointestinal, cardiac, or renal adverse effects. Several phase 2/3 studies have been accomplished for these drugs, such as tanezumab, fasinumab, and tyrosine receptor kinase A (TrkA) inhibitors. We searched the literature using the PubMed database and clinical trials using ClinicalTrials.gov to identify original papers, meta-analyses as well as ongoing clinical trials assessing the efficacy and safety profile of these drugs. In this narrative review, we briefly overview the disease burden of musculoskeletal pain, the role of NGF signaling and its receptors in the genesis of pain, and the mechanisms of action of inhibitors of NGF signaling and downstream pathways, and then discuss the efficacy and safety of each investigational drug in OA and LBP. Finally, we briefly review two serious adverse effects of NGF inhibitors, namely rapidly progressive OA and sympathetic system effects, and conclude with possible barriers and potential research directions to overcome these. [ABSTRACT FROM AUTHOR]

Given that intra-articular injections for the knee of treatments such as hyaluronic acid, stem cells and platelet-rich plasma are advised against or only weakly recommended by current clinical-practice guidelines, why do people continue to seek information about these treatments? [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a complex musculoskeletal disease and a leading cause of pain and disability worldwide. Hip and knee OA alone are major contributors to global disability, having notable effects on individual well-being, increasing the reliance of individuals on health-care services and contributing to a rise in the socioeconomic burden. Consistent, coordinated and tailored approaches are important for providing appropriate care to all people with OA, but despite the scale of the challenge many individuals are still not offered the safe, best-evidence treatments recommended for OA care. This Review discusses the core priority treatments for OA, including exercise and physical activity, weight-loss, education and support for self-management. Additional physical or psychological evidence-based adjunctive therapies and combined therapies that can be used to tailor individual programmes are also discussed. These options include cognitive behavioural therapy, heat therapy, walking aids and splints, manual therapies and transcutaneous electrical nerve stimulation. International examples of OA treatment options, models of care and resources available are also given. Many challenges still need to be addressed to advance the uptake of these conditions, including further discussion around the risks and costs involved with all treatments. [ABSTRACT FROM AUTHOR]

I was greatly honored by the invitation to give the Cutter Lecture, and following the practice of some other Cutter Lecturers I would like to offer some reflections on my career in Epidemiology, and draw some lessons about best practices that I wish I had known 35 years ago when I first considered this career. We found to our horror that the prevalence was much higher than expected, meaning that studies initially designed as cross-sectional screens designed to facilitate case-control studies could be analyzed using prevalence risk ratios and then turned into prospective studies with annual incidence rates of several percent. Reinforcement of the need for replication would come with the second grant - that funded a nested case-control study of plasma pesticide levels and breast cancer in the Nurses' Health Study. What we had not appreciated was that the established pecking order of epidemiological study designs i.e. cohort studies were superior to case-control studies, did not apply to the genetic epidemiology of main effects. [Extracted from the article]

Purpose: In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses' Health Study (NHS) and NHSII.Methods: Differential gene expression was analyzed separately in ER+ and ER− disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m2 increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent).Results: No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER− tumor and ER− tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues.Conclusions: This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms. [ABSTRACT FROM AUTHOR]

Objectives: To determine the association of superolateral Hoffa's fat pad (SHFP) oedema and patellofemoral joint structural damage in participants of Foundation for the National Institute of Health Osteoarthritis Biomarkers Consortium study.Methods: Baseline and 24-month MRIs of 600 subjects were assessed. The presence of SHFP oedema (using 0-3 grading scale) and patellar morphology metrics were determined using baseline MRI. Quantitative patellar cartilage volume and semi-quantitative MRI osteoarthritis knee score (MOAKS) variables were extracted. The associations between SHFP oedema and patellar cartilage damage, bone marrow lesion (BML), osteophyte and morphology were evaluated in cross-sectional model. In longitudinal analysis, the associations between oedema and cartilage volume loss (defined using reliable change index) and MOAKS worsening were evaluated.Results: In cross-sectional evaluations, the presence of SHFP oedema was associated with simultaneous lateral patellar cartilage/BML defects and inferior-medial patellar osteophyte size. A significant positive correlation between the degree of patella alta and SHFP oedema was detected (r = 0.259, p < 0.001). The presence of oedema was associated with 24-month cartilage volume loss (odds ratio (OR) 2.11, 95% confidence interval 1.46-3.06) and medial patellar BML size (OR 1.92 (1.15-3.21)) and number (OR 2.50 (1.29-4.88)) worsening. The optimal cut-off value for the grade of baseline SHFP oedema regarding both presence and worsening of patellar structural damage was ≥ 1 (presence of any SHFP hyperintensity).Conclusions: The presence of SHFP oedema could be considered as a predictor of future patellar cartilage loss and BML worsening, and an indicator of simultaneous cartilage, BML and osteophyte defects.Key Points: • SHFP oedema was associated with simultaneous lateral patellar OA-related structural damage. • SHFP oedema was associated with longitudinal patellar cartilage loss over 24 months. • SHFP oedema could be considered as indicator and predictor of patellar OA. [ABSTRACT FROM AUTHOR]

Objective: To determine whether 3D meniscal measures had similar sensitivity to longitudinal change as cartilage thickness; to what extent these measures are associated with longitudinal joint space width (JSW) change; and whether the latter associations differ between minimum (mJSW) and fixed-location JSW.Methods: Two-year changes in medial meniscal position and morphology, cartilage thickness (MRI) and minimum and fixed-location JSW (radiography) were determined in 35 Osteoarthritis Initiative knees [12 men, age: 67 (51-77) years; 23 women, age: 65 (54-78) years], progressing from baseline Kellgren-Lawrence grade ≤2 to knee replacement within 3-5 years. Multiple linear regression assessed the features contributing to JSW change.Results: Meniscal measures, cartilage thickness and JSW displayed similar sensitivity to change (standardised response mean≤|0.76|). Meniscal changes were strongly associated with JSW change (r≤|0.66|), adding ≤20% to its variance in addition to cartilage thickness change. Fixed-location JSW change (multiple r2=72%) was more strongly related to cartilage and meniscal change than mJSW (61%). Meniscal morphology explained more of fixed-location JSW and meniscal position more of mJSW.Conclusion: Meniscal measures provide independent information in explaining the variance of radiographic JSW change. Fixed-location JSW appears to be more reflective of structural change than mJSW and, hence, a potentially superior measure of structural progression.Key Points: • 3D positional/morphological meniscal measures change in rapidly progressing knees. • Similar sensitivity to 2-year change of quantitative meniscal/cartilage measures in rapid progression. • Changes in meniscal measures are strongly associated with radiographic JSW change. • Meniscal change provides information to explain JSW variance independent of cartilage. • Fixed-location JSW reflects structural disease stage more closely than minimum JSW. [ABSTRACT FROM AUTHOR]

Objectives: Investigating the association between baseline cartilage volume measurements (and initial 24th month volume loss) with medial compartment Joint-Space-Loss (JSL) progression (>0.7 mm) during 24-48th months of study.Methods: Case and control cohorts (Biomarkers Consortium subset from the Osteoarthritis Initiative (OAI)) were defined as participants with (n=297) and without (n=303) medial JSL progression (during 24-48th months). Cartilage volume measurements (baseline and 24th month loss) were obtained at five knee plates (medial-tibial, lateral-tibial, medial-femoral, lateral-femoral and patellar), and standardized values were analysed. Multivariate logistic regression was used with adjustment for known confounders. Artificial-Neural-Network analysis was conducted by Multi-Layer-Perceptrons (MLPs) including baseline determinants, and baseline (1) and interval changes (2) in cartilage volumes.Results: Larger baseline lateral-femoral cartilage volume was predictive of medial JSL (OR: 1.29 (1.01-1.64)). Greater initial 24th month lateral-femoral cartilage volume-loss (OR: 0.48 (0.27-0.84)) had protective effect on medial JSL during 24-48th months of study. Baseline and interval changes in lateral-femoral cartilage volume, were the most important estimators for medial JSL progression (importance values: 0.191(0.177-0.204), 0.218(0.207-0.228)) in the ANN analyses.Conclusions: Cartilage volumes (both at baseline and their change during the initial 24 months) in the lateral femoral plate were predictive of medial JSL progression.Key Points: • Baseline lateral femoral cartilage volume is directly associated with medial JSL progression. • 24-month lateral femoral cartilage loss is inversely associated with medial JSL progression. • Lateral femoral cartilage volume is most important in association with medial JSL progression. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether partial meniscectomy is associated with increased risk of radiographic osteoarthritis (ROA) and worsening cartilage damage in the following year.Methods: We studied 355 knees from the Osteoarthritis Initiative that developed ROA (Kellgren-Lawrence grade ≥ 2), which were matched with control knees. The MR images were assessed using the semi-quantitative MOAKS system. Conditional logistic regression was applied to estimate risk of incident ROA. Logistic regression was used to assess the risk of worsening cartilage damage in knees with partial meniscectomy that developed ROA.Results: In the group with incident ROA, 4.4 % underwent partial meniscectomy during the year prior to the case-defining visit, compared with none of the knees that did not develop ROA. All (n = 31) knees that had partial meniscectomy and 58.9 % (n = 165) of the knees with prevalent meniscal damage developed ROA (OR = 2.51, 95 % CI [1.73, 3.64]). In knees that developed ROA, partial meniscectomy was associated with an increased risk of worsening cartilage damage (OR = 4.51, 95 % CI [1.53, 13.33]).Conclusions: The probability of having had partial meniscectomy was higher in knees that developed ROA. When looking only at knees that developed ROA, partial meniscectomy was associated with greater risk of worsening cartilage damage.Key Points: • Partial meniscectomy is a controversial treatment option for degenerative meniscal tears. • Partial meniscectomy is strongly associated with incident osteoarthritis within 1 year. • Partial meniscectomy is associated with increased risk of worsening cartilage damage. [ABSTRACT FROM AUTHOR]

Highly prevalent among the elderly, hip osteoarthritis (OA) carries a heavy burden of disease. Guidelines for the management of hip OA are often extrapolated from knee OA research, despite clear differences in the etiopathogenesis and response to treatments of OA at these sites. We propose that hip OA requires specific attention separate from other OA phenotypes. Our understanding of the etiopathogenesis of hip OA has seen significant advance over the last 15 years, since Ganz and colleagues proposed femoroacetabular impingement (FAI) as an important etiological factor. This narrative review summarizes the current understanding of the etiopathogenesis of hip OA and identifies areas requiring further research. Therapeutic approaches for hip OA are considered in light of the condition's etiopathogenesis. The evidence for currently adopted management strategies is considered, especially those approaches that may have disease-modifying potential. We propose that shifting the focus of hip OA research and public health intervention to primary prevention and early detection may greatly improve the current management paradigm. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement.Methods: Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression.Results: One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement.Conclusions: Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement.Key Points: • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement. [ABSTRACT FROM AUTHOR]

Background: We hypothesized that not all persons with end-stage lateral osteoarthritis (OA) have valgus malalignment and that full extension radiographs may underreport radiographic disease severity. The purpose of this study was to examine the demographic and radiographic features of end-stage lateral compartment knee OA. Materials and Methods: We retrospectively studied 133 knees in 113 patients who had undergone total knee arthroplasty between June 2008 and August 2010. All patients had predominantly lateral idiopathic compartment OA according to the compartment-specific Kellgren-Lawrence grade (KLG). The mechanical axis angle (MAA), compartment-specific KLG and joint space narrowing (JSN) of the tibiofemoral joint at extension and 30° of knee flexion, tibia vara angle, tibial slope angle, body mass index, age, and sex were surveyed. Results: End-stage lateral compartment knee OA has varus (37.6 %), neutral (22.6 %), and valgus (39.8 %) MAA on both-leg standing hip-knee-ankle radiographs. KLGs at 30° of knee flexion (fKLG) were grades 3 and 4 in all patients. However, for KLGs at full extension (eKLG), 54 % of all patients had grades 3 and 4. The others (46 %) showed grades 1 and 2. We observed significant differences in lateral compartment eKLG/eJSN (2.3/2.3 mm in varus, 2.5/1.9 mm in neutral, 2.9/1.6 mm in valgus, p = 0.01 and 0.03, respectively), tibia vara angle (4.9° in varus, 4.1° in neutral, 3.0° in valgus, p < 0.01), and medial compartment eKLG/eJSN (2.1/3.1 mm in varus, 2.0/3.4 mm in neutral, 1.8/4.3 mm in valgus, p < 0.01 and 0.01, respectively) between MAA groups, except for the tibial slope angle (9.7° in varus, 10.1° in neutral, 9.8° in valgus, p = 0.31). Conclusion: Varus alignment was paradoxically shown in approximately one-third of those with end-stage lateral knee OA on both-leg standing hip-knee-ankle radiographs. Films taken in full extension underreported the degree of OA radiographic severity. Level Of Evidence: Level IV, observational study. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a highly prevalent, disabling disease, with a commensurate tremendous individual and socioeconomic burden. This Perspectives article focuses on the burden of OA for the individual, the health-care system and society, to draw attention to the magnitude of the current problem with some reference to projected figures. We have an urgent opportunity to make fundamental changes to the way we care for individuals with OA that will have an effect upon the direct and indirect costs of this disease. By focusing on the burden of this prevalent, disabling, and costly disease, we hope to highlight the opportunity for shifts in health-care policy towards prevention and chronic-disease management. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. [ABSTRACT FROM AUTHOR]

Sports participation is associated with an increased risk of future osteoarthritis (OA), much of which results from joint injury. No strong evidence exists that moderate sporting activity in the presence of normal joints predisposes to OA. Whether high-level participation in sport, particularly impact-type sports, is truly associated with OA is unclear owing to difficulties in differentiating the confounding effect of joint injury. Attention to strategies that prevent joint injury in athletes is paramount. Evidence does support the use of targeted neuromuscular exercise programmes, ankle taping and/or bracing and equipment or rule changes to prevent joint injuries in athletes. Optimal injury management, including rehabilitation and surgery if appropriate, is needed to facilitate healing and address biomechanical and neuromuscular impairments to reduce the risk of re-injury and minimize the onset and extent of joint symptoms. Management of OA in athletes requires attention to load-reducing strategies, activity modification, muscle strengthening and weight control. [ABSTRACT FROM AUTHOR]

Objective: To evaluate how the reading of knee radiographs by site investigators differs from that by an expert musculoskeletal radiologist who trained and validated them in a multicenter knee osteoarthritis (OA) study.Materials and Methods: A subset of participants from the Osteoarthritis Initiative progression cohort was studied. Osteophytes and joint space narrowing (JSN) were evaluated using Kellgren-Lawrence (KL) and Osteoarthritis Research Society International (OARSI) grading. Radiographs were read by site investigators, who received training and validation of their competence by an expert musculoskeletal radiologist. Radiographs were re-read by this radiologist, who acted as a central reader. For KL and OARSI grading of osteophytes, discrepancies between two readings were adjudicated by another expert reader.Results: Radiographs from 96 subjects (49 women) and 192 knees (138 KL grade ≥ 2) were included. The site reading showed moderate agreement for KL grading overall (kappa = 0.52) and for KL ≥ 2 (i.e., radiographic diagnosis of "definite OA"; kappa = 0.41). For OARSI grading, the site reading showed substantial agreement for lateral and medial JSN (kappa = 0.65 and 0.71), but only fair agreement for osteophytes (kappa = 0.37). For KL grading, the adjudicator's reading showed substantial agreement with the centralized reading (kappa = 0.62), but only slight agreement with the site reading (kappa = 0.10).Conclusion: Site investigators over-graded osteophytes compared to the central reader and the adjudicator. Different thresholds for scoring of JSN exist even between experts. Our results suggest that research studies using radiographic grading of OA should use a centralized reader for all grading. [ABSTRACT FROM AUTHOR]

Objective: To test the in vivo precision of a depth-specific topographic mapping technique (CT-TOMASD, computed tomography topographic mapping of subchondral density) for the 3D assessment of subchondral cortical and trabecular bone density in normal and osteoarthritic (OA) human tibiae.Methods: Fourteen participants were recruited (3 men:11 women; mean age: 49.9, SD: 11.9 years) and categorized as normal (n = 7) or OA (n = 7). Each participant was scanned using clinical quantitative CT (QCT) three times over 2 days. We assessed average subchondral bone mineral density (BMD) across three layers (0-2.5 mm, 2.5-5 mm and 5-10 mm) measured in relation to depth from the subchondral surface. Regional analyses included: medial plateau BMD; lateral plateau BMD; anterior/central/posterior compartment BMD; medial:lateral (M:L) BMD ratio; and average BMD of a 10-mm diameter "focal spot," which searched each medial and lateral plateau for the highest focal densities present within each plateau. Precision was assessed using root mean square coefficients of variation (CV%(RMS)) and intraclass correlation coefficients (ICC).Results: Average CV%(RMS) precision errors for BMD measures were 2.3%, reaching a maximum CV%(RMS) of 3.9%. ICC showed high repeatability above 0.98.Conclusions: CT-TOMASD offered precise 3D measures of subchondral BMD. This method has the potential to identify and quantify changes in subchondral BMD associated with OA in vivo. [ABSTRACT FROM AUTHOR]

Objective: Intrasubstance meniscal signal changes not reaching the articular surface on fast spin echo (FSE) sequences are considered to represent mucoid degeneration on MRI. The aim of this study was to evaluate the association of prevalent intrasubstance signal changes with incident tears of the medial meniscus detected on 3.0 T MRI over a 1-year period.Materials and Methods: A total of 161 women aged ≥ 40 years participated in a longitudinal 1-year observational study of knee osteoarthritis. MRI (3.0 T) was performed at baseline and 12-month follow-up. The anterior horn, body, and posterior horn of the medial meniscus were scored by two experienced musculoskeletal radiologists using the Boston-Leeds Osteoarthritis Knee Score (BLOKS) system. Four grades were used to describe the meniscal morphology: grade 0 (normal), grade 1 (intrasubstance signal changes not reaching the articular surface), grade 2 (single tears), and grade 3 (complex tears and maceration). Fisher's exact test and the Cochran-Armitage trend test were performed to evaluate whether baseline intrasubstance signal changes (grade 1) predict incident meniscal tears/maceration (grades 2 and/or 3) in the same subregion of the medial meniscus, when compared to subregions without pathology as the reference group (grade 0).Results: Medial meniscal intrasubstance signal changes at baseline did not predict tears at follow-up when evaluating the anterior and posterior horns (left-sided p-values 0.06 and 0.59, respectively). No incident tears were detected in the body.Conclusion: We could not demonstrate an association between prevalent medial meniscal intrasubstance signal changes with incident tears over a 1-year period. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a prevalent and disabling condition for which few safe and effective therapeutic options are available. Current approaches are largely palliative and in an effort to mitigate the rising tide of increasing OA prevalence and disease impact, modifying the structural progression of OA has become a focus of drug development. This Review describes disease modification and discusses some of the challenges involved in the discovery and development of disease-modifying OA drugs (DMOADs). A variety of targeted agents are in mature phases of development; specific agents that are beyond preclinical development in phase II and III trials and show promise as potential DMOADs are discussed. A research agenda with respect to disease modification in OA is also provided, and some of the future challenges we face in this field are discussed. [ABSTRACT FROM AUTHOR]

Objective: Changes in weight-bearing subchondral bone are central to osteoarthritis (OA) pathophysiology. Using MR, knee trabecular bone is typically assessed in the axial plane, however partial volume artifacts limit the utility of MR methods for femorotibial compartment subchondral bone analysis. Oblique-coronal acquisitions may enable direct visualization and quantification of the expected increases in femorotibial subchondral trabecular bone.Methods: MR acquisition parameters were first optimized at 3 Tesla. Thereafter, five volunteers underwent axial and coronal exams of their right knee. Each image series was evaluated visually and quantitatively. An anatomically standardized region-of-interest was placed on both the medial and lateral tibial plateaus of all coronal slices containing subchondral bone. Mean and maximum marrow signal was measured, and "bone signal" was calculated.Results: The MR acquisition had spatial resolution 0.2 × 0.2 × 1.0 mm and acquisition time 10.5 min. The two asymptomatic knees exhibited prominent horizontal trabeculae in the tibial subchondral bone, while the one confirmed OA knee had disorganized subchondral bone and absent horizontal trabeculae. The subchondral bone signal was 8-14% higher in both compartments of the OA knee than the asymptomatic knees.Conclusion: The weight-bearing femorotibial subchondral trabecular bone can be directly visualized and changes quantified in the coronal-oblique plane. Qualitative and quantitative assessments can be performed using the resultant images and may provide a method to discriminate between the healthy and OA knees. These methods should enable a quantitative evaluation of the role of weight-bearing subchondral bone in the natural history of knee OA to be undertaken. [ABSTRACT FROM AUTHOR]

Dietary intake of one-carbon nutrients (methyl donors) and germline variants in the one-carbon metabolism genes may influence global DNA methylation level and methylation in promoter CpG islands. In this study, we evaluated the relationship between single nucleotide polymorphisms (SNPs) in the one-carbon metabolism pathway and DNA methylation status in colorectal cancer. Utilizing 182 colorectal cancers cases in two prospective cohort studies, we determined the CpG island methylator phenotype (CIMP) status on eight CIMP-specific promoters and measured LINE-1 methylation level that correlates well with genome-wide DNA methylation level. We genotyped 23 nonsynonymous SNPs in the one-carbon metabolism genes using buffy coat DNA. Most of the 23 SNPs in the one-carbon metabolism pathway were not significantly associated with CIMP-high status (> or = 6/8 methylated promoters). However, the MTHFR 429 Ala/Ala variant (rs1801131) and the TCN2 259 Arg/Arg variant (rs1801198) were associated with CIMP-high status (MTHFR 429 multivariate odds ratio (MV OR) = 7.56; 95% confidence interval (CI), 1.32-43.3; p trend = 0.10; TCN2 259 Arg/Arg variant MV OR = 3.82; 95% CI, 1.02-14.4; p trend = 0.06). The one-carbon metabolism genotypes were not significantly associated with LINE-1 methylation, although there were modest differences in mean LINE-1 methylation levels between certain genotypes. Collectively, these exploratory data provide suggestive evidence for the association of MTHFR 429 Ala/ Ala and TCN2 259 Arg/Arg and CIMP status in colorectal cancer. [ABSTRACT FROM AUTHOR]

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β ( MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB. [ABSTRACT FROM AUTHOR]

Aggregate results from genome-wide association studies (GWAS), such as genotype frequencies for cases and controls, were until recently often made available on public websites because they were thought to disclose negligible information concerning an individual's participation in a study. Homer et al. recently suggested that a method for forensic detection of an individual's contribution to an admixed DNA sample could be applied to aggregate GWAS data. Using a likelihood-based statistical framework, we developed an improved statistic that uses genotype frequencies and individual genotypes to infer whether a specific individual or any close relatives participated in the GWAS and, if so, what the participant's phenotype status is. Our statistic compares the logarithm of genotype frequencies, in contrast to that of Homer et al., which is based on differences in either SNP probe intensity or allele frequencies. We derive the theoretical power of our test statistics and explore the empirical performance in scenarios with varying numbers of randomly chosen or top-associated SNPs. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment. [ABSTRACT FROM AUTHOR]

Age at menarche and age at natural menopause are associated with causes of substantial morbidity and mortality such as breast cancer and cardiovascular disease. We conducted a joint analysis of two genome-wide association studies of these two traits in a total of 17,438 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 15,151). For age at menarche, we identified ten associated SNPs (P = 1 × 10−7–3 × 10−13) clustered at 6q21 (in or near the gene LIN28B) and 9q31.2 (in an intergenic region). For age at natural menopause, we identified 13 associated SNPs (P = 1 × 10−7–1 × 10−21) clustered at 20p12.3 (in the gene MCM8), 19q13.42 (in or near the gene BRSK1), 5q35.2 (in or near genes UIMC1 and HK3) and 6p24.2 (in the gene SYCP2L). These newly identified loci might expand understanding of the biological pathways regulating these two traits. [ABSTRACT FROM AUTHOR]

The brisk discovery of novel inherited disease markers by genome-wide association (GWA) studies has raised expectations for predicting disease risk by analysing multiple common alleles. However, the statistics used during the discovery phase of research (such as odds ratios or p values for association) are not the most appropriate measures for evaluating the predictive value of genetic profiles. We argue that other measures--such as sensitivity, specificity, and positive and negative predictive values--are more useful when proposing a genetic profile for risk prediction. [ABSTRACT FROM AUTHOR]

The MDM2 oncoprotein is a key negative regulator of the tumor suppressor p53. A functional MDM2 single nucleotide polymorphism (SNP309) in the promoter region increases the affinity of transcription activator Sp1 for the MDM2 gene promoter, resulting in higher expression of MDM2 and thus inhibition of p53 transcriptional activity. UV-induced p53 activation promotes cutaneous transient pigmentation, and the common p53 Arg72Pro polymorphism alters the protein's transcriptional activity. We evaluated the effect of MDM2 SNP309 and its interaction with the p53 Arg72Pro polymorphism on pigmentary phenotypes and skin cancer risk in a nested case-control study within the Nurses' Health Study (NHS) among 219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 873 controls, and among controls from other studies. We found that the G allele of the MDM2 SNP309 was inversely associated with the presence/absence of moles on the arm among 3,207 women pooled from controls of three nested case-control studies within the NHS. Compared with the MDM2 SNP309 T/T genotype, adjusted odds ratios (ORs) of having moles on the arms for T/G and G/G genotypes were 0.92 (95% confidence interval (CI), 0.78-1.08) and 0.68 (95% CI, 0.53-0.87), respectively (p, trend, 0.005). We observed suggestive evidence of the association between the carriage of the MDM2 SNP309 G allele and childhood tanning tendency (adjusted OR, 1.30; 95% CI, 1.01-1.68). No significant associations were found between the MDM2 SNP309 and any of the three types of skin cancer. For SCC, the trend of increased risk across the three genotypes of MDM2 was stronger among p53 Pro carriers (p, trend, 0.05) than p53 Arg/Arg wild-type group (p, trend, 0.99; p, interaction, 0.07). These results provide evidence for the potential involvement of MDM2 SNP309 in pigmentary traits. [ABSTRACT FROM AUTHOR]

We evaluated the association of a polymorphism in TCF7L2 (RS12255372) in the WNT signaling pathway, which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. Hyperinsulinemia may be related to the risk of colon adenoma and cancer, therefore this variant associated with reduced insulin secretion would be predicted to be inversely associated with colorectal cancer. Overall, in the NHS and HPFS, there was suggestive evidence for an inverse association associated with homozygosity for the minor allele of RS12255372 (TCF7L2 TT) and CRC (conditional and covariate adjusted OR = 0.63, 95% CI: 0.37-1.08; P for heterogeneity 0.52 for the association in women and men). In summary, the marginal association of the TCF7L2 SNP with CRC might be due to chance, but warrants further laboratory and epidemiological investigation. [ABSTRACT FROM AUTHOR]

Recently, genome-wide association studies have identified loci across a segment of chromosome 8q24 (128,100,000–128,700,000) associated with the risk of breast, colon and prostate cancers. At least three regions of 8q24 have been independently associated with prostate cancer risk; the most centromeric of which appears to be population specific. Haplotypes in two contiguous but independent loci, marked by rs6983267 and rs1447295, have been identified in the Cancer Genetic Markers of Susceptibility project (), which genotyped more than 5,000 prostate cancer cases and 5,000 controls of European origin. The rs6983267 locus is also strongly associated with colorectal cancer. To ascertain a comprehensive catalog of common single-nucleotide polymorphisms (SNPs) across the two regions, we conducted a resequence analysis of 136 kb (chr8: 128,473,000–128,609,802) using the Roche/454 next-generation sequencing technology in 39 prostate cancer cases and 40 controls of European origin. We have characterized a comprehensive catalog of common (MAF > 1%) SNPs within this region, including 442 novel SNPs and have determined the pattern of linkage disequilibrium across the region. Our study has generated a detailed map of genetic variation across the region, which should be useful for choosing SNPs for fine mapping of association signals in 8q24 and investigations of the functional consequences of select common variants. [ABSTRACT FROM AUTHOR]

The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways. [ABSTRACT FROM AUTHOR]

Degenerative spondylolisthesis (DS) is a disorder that causes the slip of one vertebral body over the one below due to degenerative changes in the spine. Lumbar DS is a major cause of spinal canal stenosis and is often related to low back and leg pain. We reviewed the symptoms, prognosis and conservative treatments for symptoms associated with DS. PubMed and MEDLINE databases (1950–2007) were searched for the key words “spondylolisthesis”, “pseudospondylolisthesis”, “degenerative spondylolisthesis”, “spinal stenosis”, “lumbar spine”, “antherolisthesis”, “posterolisthesis”, “low back pain”, and “lumbar instability”. All relevant articles in English were reviewed. Pertinent secondary references were also retrieved. The prognosis of patients with DS is favorable, however, those who suffer from neurological symptoms such as intermittent claudication or vesicorectal disorder, will most probably experience neurological deterioration if they are not operated upon. Nonoperative treatment should be the initial course of action in most cases of DS, with or without neurologic symptoms. Treatment options include use of analgesics and NSAIDs to control pain; epidural steroid injections, and physical methods such as bracing and flexion strengthening exercises. An up-to-date knowledge on diagnosis and prevention of lumbar DS can assist in determination of future research goals. Additional studies are required to establish treatment protocols for the conservative treatment of DS. [ABSTRACT FROM AUTHOR]